Complicated UTI, stress ulcer prophylaxis, and more

Early antibiotic therapy did not improve outcomes in complicated urinary tract infection

Early antibiotic treatment for complicated urinary tract infection (UTI) did not affect
rates of treatment failure or mortality, a recent study found.

The retrospective cohort study included 981 patients with complicated UTI treated at hospitals in 20 countries in Europe and the Middle East in 2013 and 2014. The study's primary
outcome was treatment failure, which occurred in 26.6% of the patients. All-cause
30-day mortality was a secondary outcome and it occurred in 8.7% of patients, most
of whom had catheter-associated UTI. Results were published by Clinical Infectious Diseases on May 17.

Overall, patients who received early appropriate empirical antibiotic treatment had
a lower risk of treatment failure compared to patients who did not (46% vs. 55.8%; P=0.014). On multivariable analysis, neither appropriate empirical antibiotic treatment
nor days to starting antibiotics was associated with treatment failure or 30-day mortality.
Appropriate empirical antibiotic treatment was more common among patients with pyelonephritis
than in those with catheter-associated UTIs (110 of 171 patients [64.3%] vs. 116 of
270 patients [43%], P<0.005), but it was not associated with any improvement in treatment failure or
30-day mortality rates even in this subgroup.

Infection with Acinetobacter baumannii or Pseudomonas aeruginosa was associated with higher risk of treatment failure, and future research should investigate
whether the response to treatment truly differs by pathogen, the study authors said.

The results showed no benefit of early appropriate empirical treatment on survival
rates or other outcomes, the study authors concluded. “Physicians might consider
supportive treatment and watchful waiting in stable patients until the causative pathogen
is defined,” they wrote. The authors noted that other research has shown significant
benefits from early appropriate empirical treatment for bacteremia, sepsis, and septic
shock but that effects might differ in UTIs, particularly catheter-associated ones,
“as it is often difficult to distinguish between symptomatic urinary tract
infection and febrile illness from other source with asymptomatic bacteriuria, a very
common finding.”

Researchers retrospectively assessed clinically important GI bleeding episodes in 70,093 patients who had at least one risk factor for stress
ulcers and had received a PPI or H2 blocker for three or more days between Jan. 1, 2008, and June 30, 2012. Risk factors included
mechanical ventilation for more than 24 hours, coagulopathy, head injuries, major
burns, sepsis, corticosteroid therapy (≥250 mg of hydrocortisone per day or equivalent),
acute renal failure, hepatic failure, transplantation, neurological injuries, hypotension,
surgery, trauma, and ICU length of stay greater than one week. Episodes of clinically
important GI bleeding were defined by one entry of the ICD-9 code that included hematemesis,
blood in stool, and unspecified bleeding.

Overall, 49,576 (70.7%) patients received PPIs and 20,517 (29.3%) patients received
H2 blockers. The most common risk factor for stress ulcers was mechanical ventilation
(60%), and more than 50% of patients received anticoagulants, antiplatelets, or NSAIDs
during their ICU stay. There were 424 (0.6%) cases of new clinically important GI
bleeding in the cohort, which yielded an incidence rate of 1.2 cases per 1,000 patient-days
(95% CI, 1.08 to 1.31). After adjustment for potential confounders, the PPI group
had a nearly twofold higher risk of clinically important GI bleeding than the H2 blocker
group (hazard ratio, 1.97; 95% CI, 1.48 to 2.63).

Other factors associated with a higher risk of GI bleeding included male gender (hazard
ratio [HR], 1.27; 95% CI, 1.04 to 1.54), acute renal failure (HR, 1.59; 95% CI, 1.28
to 1.97), receipt of sucralfate (HR, 3.25; 95% CI, 2.18 to 4.85), and receipt of an
antiplatelet agent (HR, 1.35; 95% CI, 1.01 to 1.79). Having a surgical procedure or
being a trauma victim was associated with a lower risk of clinically important GI
bleeding (HR, 0.46; 95% CI, 0.25 to 0.84). The study was published online on May 29
by CHEST and appeared in the September issue.

The study authors noted limitations, such as the fact that exposure to PPIs or H2
blockers was not randomly assigned and that confounding factors related to the tendency
of an ICU to preferentially prescribe a PPI may have been present. Despite these limitations,
the findings “support the conclusions of cost-effectiveness studies that favor
the use of [an H2 blocker] over a PPI for stress ulcer prophylaxis of at risk critically
ill adults,” they concluded.

A biomarker, amyloid-β (1-40) (Aβ40), may improve risk stratification
in patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS), according
to a retrospective study.

Researchers used data from two European cohort studies of patients hospitalized with NSTE-ACS: the Heidelberg study (n=1145) and, for validation, the Advantageous Predictors of Acute Coronary Syndrome
Evaluation (APACE) study (n=734). Median follow-up was 21.9 months and 24.9 months, respectively. Results were
published online by Annals of Internal Medicine on May 22 and appeared in the June 19 issue.

Using Aβ40 to determine patients' risk correctly reclassified both cohorts compared
to the GRACE score (net reclassification index, 33.4% and 47.1% for the Heidelberg
and APACE cohorts, respectively; P<0.05). “The novel finding of this study is that a single measurement of
Aβ40 at presentation with NSTE-ACS confers prognostic value and correctly reclassifies
patients into risk categories for mortality and a composite of death or nonfatal [myocardial
infarction] over the GRACE score, which is widely recommended by clinical guidelines
for accurate risk stratification,” the authors said.

They noted that accurate early risk stratification is important for making decisions
about which patients require urgent interventional treatment, so this could be a useful
biomarker. The authors did caution that concentrations of Aβ40 may be affected
by the antibody used in testing as well as storage and preparation of samples and
that researchers will therefore need to determine reference values before the biomarker
can be used in clinical practice. The authors also called for research to determine
whether Aβ40 could be a therapeutic target to prevent ACS or improve outcomes
after it has occurred.

Patients with minor ischemic stroke or high-risk transient ischemic attack (TIA) were
less likely to have a major ischemic event at 90 days but more likely to have a major
hemorrhage with combination antiplatelet therapy than with aspirin alone, according
to a recent study.

Overall, a total of 4,881 patients were enrolled in the study, 2,432 of whom received
combination therapy and 2,449 of whom received placebo plus aspirin. Most of the patients,
82.8%, were in the U.S. Major ischemic events occurred in 121 and 160 patients in
each group (5.0% and 6.5%, respectively; hazard ratio [HR], 0.75; P=0.02), most commonly within the first week after the initial stroke or TIA. Ischemic
stroke, a secondary outcome, occurred in 112 patients in the combination therapy group
and 155 patients in the aspirin group (4.6% vs. 6.3%; HR, 0.72; P=0.01). Twenty-three patients in the combination therapy group and 10 patients in
the aspirin group developed major hemorrhage (0.9% vs. 0.4%; HR, 2.32; P=0.02). The trial was stopped early by the data monitoring board due to excess hemorrhage
risk in the combination therapy group and evidence of treatment efficacy.

The researchers noted that their trial did not include patients who had moderate to
severe stroke or cardioembolic stroke or those who were candidates for thrombolysis
or thrombectomy and that aspirin doses were determined by the clinical judgment of
each site's investigator, among other limitations. However, they concluded that combination
therapy with clopidogrel and aspirin was associated with a lower risk of the composite
outcome but a higher risk of major bleeding versus aspirin alone over the initial
90-day period. They estimated that for every 1,000 similar patients treated with clopidogrel
plus aspirin for 90 days, approximately 15 ischemic events would be prevented and
five major hemorrhages would be caused.

The author of an accompanying editorial noted that although the study results might
suggest no net benefit with combination therapy, most of the events that were prevented
were ischemic stroke, “the most common and arguably most important of the outcomes
after a TIA or minor stroke,” and most of the bleeding complications were nonfatal.
He also pointed out the timing of the outcomes. “Most of the benefit regarding
stroke prevention occurred in the first week of treatment with the combination, whereas
most of the bleeding occurred later,” he wrote.

The take-home message for clinicians from this and related research, the editorialist said, is that aspirin plus clopidogrel reduces risk for recurrent ischemic
stroke during a high-risk period immediately after a TIA or noncardioembolic ischemic stroke
but that it should be used only for the first three weeks before transitioning to
monotherapy. He noted that dual therapy should not be recommended for patients for
whom follow-up and adherence are uncertain and may not be advisable in patients with
an uncertain diagnosis of TIA or in patients at increased risk for bleeding.

BNP predicts mortality, even in patients without heart failure

Researchers used data from the Vanderbilt University Medical Center electronic health
record to identify 30,487 patients who had a first plasma BNP measurement between 2002 and 2013. Their median age was 63 years, 50% were men, 17% were black,
and 38% were diagnosed with heart failure. Follow-up continued through 2015, and results
were published in the May 15 Journal of the American College of Cardiology.

Over 90,898 person-years of follow-up, 31% of the patients without heart failure and
53% of those with heart failure died. BNP levels were lower in patients without heart
failure than in those with heart failure (median, 89 pg/mL [interquartile range, 34
to 238 pg/mL] vs. 388 pg/mL [interquartile range, 150 to 940 pg/mL]; P<0.0001). However, the risk for death according to BNP level was similar regardless
of whether patients had heart failure. For example, a BNP level of 400 pg/mL was associated
with a three-year risk for death of 21% (95% CI, 20% to 23%) in patients with heart
failure and 19% (95% CI, 17% to 20%) in those without.

This increase in mortality was observed whether patients' elevated BNP level was found
in an acute care or outpatient setting. Higher BNP level was the strongest predictor
of mortality risk among patients without heart failure, even in multivariate models
including traditional risk markers such as age, renal function, diabetes, vital signs,
left ventricular mass, and left ventricular ejection fraction. The authors noted that
the latter two factors were found to be strongly associated with higher BNP levels.
“Thus, finding an elevated BNP level in a patient without [heart failure] may
warrant additional investigation, including assessment of cardiac structure and function,”
the authors said.

They cautioned that as an observational analysis, the study is susceptible to residual
confounding, and that other potentially predictive factors, such as C-reactive protein
and troponin, were not compared to BNP. Variability in treatment, such as high diuretic
doses for patients with acute heart failure decompensation, may also have affected
BNP levels, they noted.

An accompanying editorial called the results “stimulating” and offered several possible
explanations for the prognostic value of BNP in patients without heart failure. Elevated BNP levels
could be a sign of asymptomatic cardiac disease, an effect of noncardiac conditions
such as sepsis or chronic obstructive pulmonary disease, or a sign of vascular aging.
Based on the study's findings, the editorialists recommended more extensive cardiovascular
evaluation for patients found to have BNP levels above 35 pg/mL in outpatient settings
or above 100 pg/mL in acute care. They noted that the next question for researchers
will be how to treat patients who have an elevated BNP level without heart failure.

Researchers compared opioid use between a six-month control period (n=287 patients) and a three-month intervention period (n=127 patients). The primary outcome was the number of IV doses administered per patient-day.
Secondary outcomes included total parenteral and overall opioid doses per patient-day,
parenteral and overall opioid exposure per patient-day, and daily rate of patients
receiving parenteral opioids. Researchers also measured pain scores on a 0 to 10-point
Likert scale during the first five days of hospitalization and compared them between
groups. Results were published online on May 14 by JAMA Internal Medicine and appeared in the June issue.

The control period included 4,500 patient-days, and the intervention period included
2,459 patient-days. During the intervention, 65% of parenteral opioid doses were administered
subcutaneously, compared with fewer than 1% during the control period. IV opioid doses
decreased by 84% from the control to the intervention period (0.39 vs. 0.06 doses
per patient-day; P<0.001).

There were no significant differences in patients' mean reported pain scores for hospital
days 1 through 3, but there was significant improvement in the intervention group
on day 4 (4.82 vs. 3.75; difference, −1.07; 95% CI, −1.80 to −0.34; P=0.004) and on day 5 (4.65 vs. 3.59; difference, −1.06; 95% CI, −1.84
to −0.27; P=0.009).

The study authors noted limitations, such as how the intervention was a pilot project
conducted on a single unit at one academic medical center. In addition, prescribers
in specialties other than internal medicine did not participate in the study, which
may limit generalizability, and pain scores may not have captured discomfort associated
with subcutaneous administration, they noted.

The authors added that the results occurred without any changes to the electronic
health record, which could potentially increase its effects. “This intervention
should be scalable to larger populations of inpatients, and future directions may
include study in other areas of hospital practice, including the surgical, emergency,
obstetric, pediatric, and critical care environments,” they wrote.

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